Renal cell carcinoma in adult patients with thalassaemia major: a description of three cases

Abstract

There is accumulating evidence that, because of iron loading, patients with thalassaemia are also prone to develop cancer and that in this category of closely followed patients, cancer is probably diagnosed more frequently and earlier in the disease course as compared to general population (Govoni et al, 2011; Ricchi et al, 2014). In our centre, we have been routinely following approximately 100 adult thalssaemia major (TM) patients since childhood. During these years of observation, patients underwent abdominal ultrasound (US), once yearly to assess the size and location of abdominal organs or twice yearly to monitor those affected by chronic hepatitis C virus (HCV) infection. Herein we report three cases of renal cell carcinoma (RCC) detected incidentally without any symptoms on abdominal US; Table 1 shows their clinical features and pathological findings. There is an increasing body of evidence that, in patients with TM or thalassaemia intermedia, haematological and non-haematological malignancies are becoming more frequent, but no cases of RCC in patients affected by β-TM have been yet reported. Recently, because of the increasing age of patients with TM, renal disease has become a challenging issue; however, most recent studies have focused on the potential link between iron accumulation, iron chelation and kidney dysfunction but probably have under-evaluated the latent problem of cancer. RCC represents 2–3% of all cancers in the general population, with an incidence of 6–12 cases per 100 000 people in Western countries and with a peak incidence occurring between 60 and 70 years of age. Well-recognized aetiological factors include lifestyle factors, such as smoking, obesity and antihypertensive therapy (Bergstrom et al, 2001; Lindblad, 2004). As a result of the increased detection of tumours by the use of imaging techniques, such as ultrasound (US) and computerized tomography (CT), there is an increasing number of incidentally diagnosed RCCs, often presenting with lower stage, grade and percentage of metastases (Tsui et al, 2000); conversely, in our series, we observed three cases of RCC in our adult patients with TM, which translates into a prevalence of RCC of 3%. More interestingly, all three cases detected were approximately 40 years old and the disease was particularly aggressive in two of them, being identified at a relatively advanced stage. It is notable that such a prevalence rate of renal neoplasm was not observed among our population of approximately 95 patients with non-transfusion dependent thalassaemia (NTDT) of comparable age who were also periodically evaluated by US scan (data not shown). Thus, it should not be concluded that such tumours were found because of the extensive use of full abdominal US, and it is conceivable that, because of the advanced stage, two of these patients would soon have become symptomatic without US scanning. However, the younger age at the presentation with respect to that usually found in the general population may suggest the presence of a risk factor in our series: further studies are needed to clarify if iron overload per se, some other factor(s) linked to thalassaemia or simply receiving regular transfusions could be involved in this higher-than-expected prevalence. Post-mortem studies of regularly transfused patients have described haemosiderin deposition in visceral and parietal glomerular epithelial cells in both proximal and distal convoluted tubules (Landing et al, 1989) and this has been associated with cellular damage via stimulation of reactive oxidative elements in rats (Zhou et al, 2000). Alternatively, it has been recently shown that hypoxia-inducible factors are not only activated in the normal kidney under conditions of systemic and regional hypoxia (Haase, 2013), but that they also play an important role in renal tumourigenesis and renal cystic transformation (Eckardt et al, 2007) being constitutively activated in the majority of clear cell RCC cases (Baldewijns et al, 2010). Further studies are needed to clarify the level of activation of the hypoxia-inducible factor system in normal and cancer renal tissue in regularly transfused TM patients in order to determine whether TM could represent a pre-neoplastic state at renal level in which the iron-induced oxidative damage may act as an important factor for additional tumour progression.